(PQ10) Do microbiota alter the epigenetic landscape in human genome

(PQ10) 微生物群会改变人类基因组的表观遗传景观吗

• 批准号: 9171885
• 负责人: Alex Y Strongin
• 金额: $ 25.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-13 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171885
• 关键词: Aberrant DNA Methylation; Address; Affect; Antibiotic Therapy; Bacteria; Benign; Biology; Cancer Biology; Cell Nucleus; Cell Wall; Cells; Chromosome Mapping; Chronic; Clinical; Colon; Colorectal Cancer; CpG Islands; CpG dinucleotide; Cytolysis; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; Data; Development; Disease; Enzymes; Epigenetic Process; Epithelial Cells; Evolution; Exploratory/Developmental Grant; Funding; Genes; Genetic; Genome; Genomic DNA; Genomics; Germ-Line Mutation; Goals; Habitats; Health; Human; Human Biology; Human Genome; Human body; Immune; Incidence; Individual; Infection; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Methodology; Methylation; Methyltransferase; Modification; Mycoplasma; Mycoplasma Infections; Mycoplasma hyorhinis; Nature; Neoplastic Cell Transformation; Oncogenic; Organism; Osmotic Shocks; Patients; Penicillin Resistance; Phenotype; Positioning Attribute; Probability; Promoter Regions; Property; Proteins; Research; Role; Site; Somatic Mutation; Staging; Stem cells; System; Therapeutic; Tissue Sample; Tissues; Tumor Biology; Work; base; cancer cell; cancer risk; cancer stem cell; cancer therapy; cancer type; data mining; epigenome; genome-wide; human tissue; in vivo; innovation; microbial; microbiome; microbiota; novel; novel diagnostics; pathogen; pathogenic bacteria; precursor cell; prognostic; programs; response; trafficking; tumor; tumorigenesis; tumorigenic

PROJECT SUMMARY This application is in response to RFA-CA-15-009 to propose pioneering approaches to addressing PQ–10 “How do microbiota affect the response to cancer therapies?” Human biology is no longer focused only on human cells. Microbiomes at different body habitats are now considered an essential component of human biology, development, evolution, health and disease. Bacteria of the endogenous flora in the human body outnumber human cells by at least one order of magnitude. A plethora of symbiotic and pathogenic bacteria in different body habitats form the microbiome. Bacteria, including mycoplasmas, internalize and colonize human cells, thereby subverting the immune defense system and antibiotic treatment. Mycoplasmas are the smallest and simplest self-replicating organisms. Over 200 species of mycoplasma are distinguished from ordinary bacteria by their minute size, limited genome, and lack of a cell wall. The absence of a cell wall conveys some unique properties to mycoplasma including their resistance to penicillin and sensitivity to lysis and osmotic shock. The data by us and others imply that mycoplasma infections are associated with some cancer types, including colorectal cancer. This suggests the possible co-existence of mycoplasmas and tumors in vivo that affects the response to cancer therapies, or, alternatively, indicates that mycoplasma infections create a possible roadmap to multi-step malignant transformation via epigenetic reprogramming of the affected normal/stem cells. Our working hypothesis is that chronic mycoplasma infection in the gut eventually leads to epigenetic alterations in epithelial cells that may enhance the likelihood for neoplastic transformation. An alternative, but not an exclusive hypothesis, is that the mycoplasma infection accelerates an already on-going tumorigenesis through the induction of additional epigenetic abnormalities. Our goals are to pursue this innovative hypothesis. Our R21 program is based on volumes of our innovative experimental data characterizing epigenetic abnormalities, which are aberrantly introduced in the human genome by mycoplasmal 5-methylcytosine-DNA methyltransferases. Our Specific Aims are: (1) Demonstrate the presence of the aberrant, de novo genomic DNA methylation in host cells infected by M. hyorhinis, and (2) Determine the incidence of the genomic material of Mycoplasma hyorhinis and other mycoplasma species in tumor and normal human tissue samples. We are confident that our proposed studies will lead to paradigm- shifting results in host-pathogen interactions, human epigenetics and cancer onset, and that our project will have wide-ranging ramifications. Additionally, this knowledge will lead to novel diagnostic and prognostic approaches and therapeutic regiments in patients at risk of cancer development.

项目摘要 该应用程序是对RFA-CA-15-009的响应 “微生物群如何影响对癌症疗法的反应？”人类生物学不再仅专注于 人类细胞。现在，不同人体栖息地的微生物组被认为是人类的重要组成部分 生物学，发展，进化，健康和疾病。人体内源性菌群的细菌 人数超过人类细胞至少一个数量级。多种共生和致病细菌 不同的身体栖息地形成微生物组。细菌，包括支原体，内化和定居人 细胞，从而颠覆免疫防御系统和抗生素治疗。分支机构是最小的 和最简单的自我复制生物。超过200种的支原体与普通区分开 细菌按微小的大小，有限的基因组和缺乏细胞壁。缺少细胞壁会传达一些 分枝菌的独特特性，包括它们对青霉素的耐药性以及对裂解和渗透的敏感性 震惊。我们和其他人的数据表明，支原体感染与某些癌症类型有关， 包括结直肠癌。这表明体内支原体和肿瘤可能存在 影响对癌症疗法的反应，或者，或者表明支原体感染会产生 通过表观遗传重新编程，可能的路线图可能会导致多步恶性转化 正常/干细胞。我们工作的假设是肠道中的慢性支原体感染最终导致 上皮细胞的表观遗传学改变，可能会增强肿瘤转化的可能性。一个 替代方案，但不是独家假设，是支原体感染加速了已经持续的 肿瘤发生通过诱导其他表观遗传异常。我们的目标是追求 创新假设。我们的R21程序基于我们创新的实验数据的卷 表征表观遗传异常，这些异常被异常引入人类基因组中 支原体5-甲基环胞嘧啶-DNA甲基转移酶。我们的具体目的是：（1）证明 在被hyorhinis感染的宿主细胞中存在异常，从头基因组DNA甲基化，（2） 确定支原体hyorhinis和其他支原体物种的基因组材料的事件 肿瘤和正常的人体组织样品。我们相信我们的拟议研究将导致范式 - 转移导致宿主 - 病原体相互作用，人类表观遗传学和癌症发作，我们的项目将 有广泛的后果。此外，这些知识将导致新颖的诊断和预后 患有癌症发展风险的患者的方法和治疗团。